GMP manufacture and Phase I clinical trial of a thermostable single-dose rabies vaccine for pre-exposure prophylaxis for children in endemic areas
Lead Research Organisation:
University of Oxford
Department Name: The Jenner Institute
Abstract
Although rabies is one of the first diseases for which effective vaccines were developed, it still kills more than 50,000 people every year- mostly children in developing countries in South Asia and Africa who are bitten by rabid dogs. The disease is unique among human viral infections in that it has a 100% fatality rate: infected people suffer a slow and terrifying death.
The reason that the problem persists on this scale is that currently available rabies control tools have major shortcomings. Current vaccines, based upon killed rabies viruses, have changed relatively little from the first rabies vaccine administered by Pasteur in 1885. They are too expensive to be given to whole populations as part of routine childhood vaccination packages, partly because they require refrigeration and need multiple doses to achieve protection. The combination of vaccine and antibody treatment needed if an unvaccinated child is bitten by a dog which might be rabid is even more expensive and not reliably available- so many people are forced to take the risk of going without treatment. Vaccinating dogs can be very effective, but in many areas, there is a lack of veterinary health infrastructure or the behaviour patterns of dogs make them difficult to reach.
This project aims to test in humans a new rabies vaccine which we have produced using modern techniques. This new vaccine will be considerably cheaper than current vaccines, will not require refrigeration, and will only require a single dose. As such, it should be suitable for mass vaccination of all children at risk of rabies.
Our vaccine consists of a version of a common cold virus which cannot grow in the human body but exposes the body's immune system to the major protein building block of the rabies virus' coat. By doing this, it stimulates the immune system to produce antibodies that are capable of killing the rabies virus. We have shown in studies in experimental animals that a small dose of our vaccine is sufficient to protect the animals against infection with rabies for nearly two years.
The other key part of this project involves the stabilisation of the vaccine by drying it in a defined sugar solution on a paper-like membrane- a technique inspired by the ability of certain sugar-containing plants to survive in hot, dry conditions. The dried vaccine is able to withstand high temperatures, instead of needing refrigeration or freezing. This will make the distribution of vaccine to low-resource areas considerably cheaper and more reliable. Importantly, the drying technique is very straightforward and could be applied to many other vaccines- our intention is that this study, using our new rabies vaccine, will provide a proof-of-concept encouraging the technique to be adopted for other vaccines.
We have already manufactured the vaccine in the laboratory and (as stated above) have shown that it is highly effective in animals. This project will allow us to manufacture the vaccine to the stricter standards known as 'Good Manufacturing Practice', which are needed in order to make a 'pharmaceutical-grade' product which can be tested in human trials. We will produce 'pharmaceutical-grade' versions of the vaccine in both conventional liquid form and the dried, thermostable form. The final part of the project will be to test the vaccines carefully for safety in a clinical trial in healthy British adult volunteers. This will also allow us to compare the two forms of our vaccine with each other and with an existing rabies vaccine for their ability to induce anti-rabies antibodies. Good results in this trial will allow the vaccine to progress into further trials in children in countries which have major rabies problems.
The reason that the problem persists on this scale is that currently available rabies control tools have major shortcomings. Current vaccines, based upon killed rabies viruses, have changed relatively little from the first rabies vaccine administered by Pasteur in 1885. They are too expensive to be given to whole populations as part of routine childhood vaccination packages, partly because they require refrigeration and need multiple doses to achieve protection. The combination of vaccine and antibody treatment needed if an unvaccinated child is bitten by a dog which might be rabid is even more expensive and not reliably available- so many people are forced to take the risk of going without treatment. Vaccinating dogs can be very effective, but in many areas, there is a lack of veterinary health infrastructure or the behaviour patterns of dogs make them difficult to reach.
This project aims to test in humans a new rabies vaccine which we have produced using modern techniques. This new vaccine will be considerably cheaper than current vaccines, will not require refrigeration, and will only require a single dose. As such, it should be suitable for mass vaccination of all children at risk of rabies.
Our vaccine consists of a version of a common cold virus which cannot grow in the human body but exposes the body's immune system to the major protein building block of the rabies virus' coat. By doing this, it stimulates the immune system to produce antibodies that are capable of killing the rabies virus. We have shown in studies in experimental animals that a small dose of our vaccine is sufficient to protect the animals against infection with rabies for nearly two years.
The other key part of this project involves the stabilisation of the vaccine by drying it in a defined sugar solution on a paper-like membrane- a technique inspired by the ability of certain sugar-containing plants to survive in hot, dry conditions. The dried vaccine is able to withstand high temperatures, instead of needing refrigeration or freezing. This will make the distribution of vaccine to low-resource areas considerably cheaper and more reliable. Importantly, the drying technique is very straightforward and could be applied to many other vaccines- our intention is that this study, using our new rabies vaccine, will provide a proof-of-concept encouraging the technique to be adopted for other vaccines.
We have already manufactured the vaccine in the laboratory and (as stated above) have shown that it is highly effective in animals. This project will allow us to manufacture the vaccine to the stricter standards known as 'Good Manufacturing Practice', which are needed in order to make a 'pharmaceutical-grade' product which can be tested in human trials. We will produce 'pharmaceutical-grade' versions of the vaccine in both conventional liquid form and the dried, thermostable form. The final part of the project will be to test the vaccines carefully for safety in a clinical trial in healthy British adult volunteers. This will also allow us to compare the two forms of our vaccine with each other and with an existing rabies vaccine for their ability to induce anti-rabies antibodies. Good results in this trial will allow the vaccine to progress into further trials in children in countries which have major rabies problems.
Technical Summary
The belief that rabies is a bygone disease for which an adequate vaccine exists is incorrect. Global rabies mortality is c. 59,000/year. Existing control measures are inadequate: current human vaccines are too expensive for mass use, and canine vaccination is challenging in many settings.
We have developed a replication-deficient simian adenovirus vaccine encoding rabies glycoprotein. In a non-human primate trial, this outperformed the current human rabies vaccine: a single dose protected 100% of animals challenged 22 months after vaccination. The immunogenicity of the vaccine is such that the dose required to protect primates is 50-fold less than typically used for other adenovirus-based vaccines in humans. Moreover, we have developed an inexpensive thermostabilisation process to facilitate vaccine distribution. The vaccine will thus be sufficiently cheap to permit mass pre-exposure vaccination in rabies endemic low/middle-income countries, dramatically reducing mortality.
Importantly, the project will provide clinical proof of concept for the thermostabilisation technology. The approach is applicable to other vaccines, out-performing lyophilisation and potentially enhancing reach and cost-efficacy by removing the need for expensive cold-chain distribution.
We propose a milestone-based approach comprising
1. Process development
2. GMP manufacture of adenovirus; pre-GMP thermostabilisation tech transfer
3. GMP manufacture of thermostable formulation; pre-trial preparation (QC, toxicology, regulatory & ethics)
4. Phase I trial comparing standard v. stabilised adenovirus v. existing rabies vaccine.
Post-DPFS development would piggyback upon trials of adenovirus-based malaria vaccines in children in Africa. Rabies vaccine licensure is based upon a surrogate of protection (in vitro virus neutralisation) and thus achievable without a large trial to directly demonstrate efficacy.
The application is accompanied by a letter of support from the WHO.
We have developed a replication-deficient simian adenovirus vaccine encoding rabies glycoprotein. In a non-human primate trial, this outperformed the current human rabies vaccine: a single dose protected 100% of animals challenged 22 months after vaccination. The immunogenicity of the vaccine is such that the dose required to protect primates is 50-fold less than typically used for other adenovirus-based vaccines in humans. Moreover, we have developed an inexpensive thermostabilisation process to facilitate vaccine distribution. The vaccine will thus be sufficiently cheap to permit mass pre-exposure vaccination in rabies endemic low/middle-income countries, dramatically reducing mortality.
Importantly, the project will provide clinical proof of concept for the thermostabilisation technology. The approach is applicable to other vaccines, out-performing lyophilisation and potentially enhancing reach and cost-efficacy by removing the need for expensive cold-chain distribution.
We propose a milestone-based approach comprising
1. Process development
2. GMP manufacture of adenovirus; pre-GMP thermostabilisation tech transfer
3. GMP manufacture of thermostable formulation; pre-trial preparation (QC, toxicology, regulatory & ethics)
4. Phase I trial comparing standard v. stabilised adenovirus v. existing rabies vaccine.
Post-DPFS development would piggyback upon trials of adenovirus-based malaria vaccines in children in Africa. Rabies vaccine licensure is based upon a surrogate of protection (in vitro virus neutralisation) and thus achievable without a large trial to directly demonstrate efficacy.
The application is accompanied by a letter of support from the WHO.
Planned Impact
The main direct benefit of this project is intended to be the provision of a tool for reduction in global rabies mortality, and as such, the main direct beneficiaries would be the recipients of the vaccine we intend to develop. We anticipate that benefits would accrue both via the avoidance of the terrifying and fatal illness of rabies itself, and via a reduction in the costs associated with rabies prophylaxis (notably a reduction in the requirement for extremely expensive rabies immune globulin following animal bites). A realistic timescale for the delivery of this benefit- allowing for subsequent clinical trials and licensure- is c. 10 years from the initiation of the project.
As described in the downstream development sections of the Case for Support, later-stage development of the vaccine would be undertaken with commercial partners. The size of the potential market for rabies vaccines is large and we anticipate that such partners would be able to secure a commercial return. As well as this direct commercial benefit, the project will further promote the UK's strategic excellence in vaccine development, a major business area for UK-based pharmaceutical companies.
The cost-effectiveness of a thermo-stable rabies vaccine will be crucial to its eventual deployment in rabies-endemic areas, which are in low and middle income countries. This issue is addressed in more detail in section 5.1 of the Case for Support, where we conclude that cost equilibrium for PrEP and PEP (pre and post exposure prophylaxis respectively) would be reached if a PrEP vaccine cost less than USD 4 per course. Current calculations estimate the final cost of a thermo-stable ChAdOx2-RabGP vaccine to be less than USD 2 per dose (including GMP manufacture, and a vaccine storage and delivery device). If funded, we will work during the project with vaccine manufacturers and with economists at the Said Business School in Oxford to calculate more accurately the predicted cost of manufacture of thermo-stable ChAdOx2-RabGP produced at a large scale, suitable for mass immunisation campaigns.
Indirect academic beneficiaries are described in the separate section above and would include vaccine developers targeting other disease indications, who would benefit from the development of the ChAdOx2 and thermostabilisation platform technologies. Other economic beneficiaries are companies and/or manufacturing organisations producing thermo-stable vaccines in both the developed world and resource-poor countries, which would benefit from production of cheap, stable vaccines with reduced losses from vaccine instability during transport and storage.
As described in the downstream development sections of the Case for Support, later-stage development of the vaccine would be undertaken with commercial partners. The size of the potential market for rabies vaccines is large and we anticipate that such partners would be able to secure a commercial return. As well as this direct commercial benefit, the project will further promote the UK's strategic excellence in vaccine development, a major business area for UK-based pharmaceutical companies.
The cost-effectiveness of a thermo-stable rabies vaccine will be crucial to its eventual deployment in rabies-endemic areas, which are in low and middle income countries. This issue is addressed in more detail in section 5.1 of the Case for Support, where we conclude that cost equilibrium for PrEP and PEP (pre and post exposure prophylaxis respectively) would be reached if a PrEP vaccine cost less than USD 4 per course. Current calculations estimate the final cost of a thermo-stable ChAdOx2-RabGP vaccine to be less than USD 2 per dose (including GMP manufacture, and a vaccine storage and delivery device). If funded, we will work during the project with vaccine manufacturers and with economists at the Said Business School in Oxford to calculate more accurately the predicted cost of manufacture of thermo-stable ChAdOx2-RabGP produced at a large scale, suitable for mass immunisation campaigns.
Indirect academic beneficiaries are described in the separate section above and would include vaccine developers targeting other disease indications, who would benefit from the development of the ChAdOx2 and thermostabilisation platform technologies. Other economic beneficiaries are companies and/or manufacturing organisations producing thermo-stable vaccines in both the developed world and resource-poor countries, which would benefit from production of cheap, stable vaccines with reduced losses from vaccine instability during transport and storage.
Publications
Wang C
(2018)
A simian-adenovirus-vectored rabies vaccine suitable for thermostabilisation and clinical development for low-cost single-dose pre-exposure prophylaxis.
in PLoS neglected tropical diseases
Dulal P
(2021)
Characterisation of factors contributing to the performance of nonwoven fibrous matrices as substrates for adenovirus vectored vaccine stabilisation
in Scientific Reports
Zhang C
(2023)
Lyophilization to enable distribution of ChAdOx1 and ChAdOx2 adenovirus-vectored vaccines without refrigeration.
in NPJ vaccines
Joe CCD
(2022)
Manufacturing a chimpanzee adenovirus-vectored SARS-CoV-2 vaccine to meet global needs.
in Biotechnology and bioengineering
Ng WM
(2022)
Structure of trimeric pre-fusion rabies virus glycoprotein in complex with two protective antibodies.
in Cell host & microbe
Description | COVID-19 vaccine manufacturing |
Geographic Reach | Multiple continents/international |
Policy Influence Type | Membership of a guideline committee |
Impact | The Douglas group developed the original manufacturing process for the Oxford/AstraZeneca COVID-19 vaccine, and supported it's scale up and roll out with AstraZeneca. The foundational work for this was provided by several awards to the Douglas group in recent years. |
Description | WHO expert committee meeting on Rabies, December 2022 |
Geographic Reach | Multiple continents/international |
Policy Influence Type | Participation in a guidance/advisory committee |
Description | Clarendon |
Amount | £0 (GBP) |
Organisation | University of Oxford |
Sector | Academic/University |
Country | United Kingdom |
Start | 09/2018 |
End | 09/2021 |
Description | GCRF open internal competition |
Amount | £45,300 (GBP) |
Organisation | Higher Education Funding Council for England |
Sector | Public |
Country | United Kingdom |
Start | 02/2018 |
End | 07/2018 |
Description | International Veterinary Vaccinology Network |
Amount | £80,460 (GBP) |
Funding ID | MC_PC_17219 |
Organisation | Medical Research Council (MRC) |
Sector | Public |
Country | United Kingdom |
Start | 03/2018 |
End | 04/2019 |
Description | Marie Sklodowska-Curie Individual Fellowships |
Amount | € 224,934 (EUR) |
Organisation | European Commission |
Sector | Public |
Country | European Union (EU) |
Start | 06/2019 |
End | 06/2021 |
Description | Rapid development of manufacturing processes for future production of adenovirus-vectored COVID19 vaccine at million-dose scale |
Amount | £411,388 (GBP) |
Funding ID | MC_PC_19058 |
Organisation | Medical Research Council (MRC) |
Sector | Public |
Country | United Kingdom |
Start | 03/2020 |
End | 09/2020 |
Description | The Future Vaccine Manufacturing Research Hub (Vax-Hub) |
Amount | £6,968,180 (GBP) |
Funding ID | EP/R013756/1 |
Organisation | Engineering and Physical Sciences Research Council (EPSRC) |
Sector | Public |
Country | United Kingdom |
Start | 03/2018 |
End | 03/2021 |
Description | Understanding and inducing immunity against rabies and Epstein Barr virus Class III fusion proteins |
Amount | £1,304,625 (GBP) |
Funding ID | 220679/Z/20/Z |
Organisation | Wellcome Trust |
Sector | Charity/Non Profit |
Country | United Kingdom |
Start | 01/2021 |
End | 12/2025 |
Title | Development of manufacturing process for ChAdOx vaccines, applied to the Oxford-AstraZeneca COVID-19 vaccine |
Description | New Upstream and Downstream methods for manufacturing and purifying ChAdOx vaccines at industrial scale. This has been used to make over 2.5billion doses of the Oxford-AZ vaccine (by March 2022) |
Type Of Material | Technology assay or reagent |
Year Produced | 2020 |
Provided To Others? | Yes |
Impact | 2.5 billion doses of vaccine to date |
Description | EMD Millipore |
Organisation | Merck |
Department | MilliporeSigma |
Country | United States |
Sector | Private |
PI Contribution | Our research team have been developing new upstream and downstream processes for adenovirus vaccine production at the Clinical Biomanufacturing Facility. |
Collaborator Contribution | The MilliporeSigma/Merck group have contributed financial support for the project, equipment and materials they produce required for the project, and expertise required to develop the project. |
Impact | More advanced processes for GMP manufacture of adenovirus vectored vaccines have been developed. These will be used in the manufacture of the ChAdOx2 RabG vaccine that is being produced with support of this grant. A paper has been submitted to the journal Vaccine. Once accepted this will be added to the publications section. |
Start Year | 2018 |
Description | NIRI matrices |
Organisation | Nonwovens Innovation & Research Institute Ltd |
Country | United Kingdom |
Sector | Private |
PI Contribution | Our research team has provided vaccine-side input and guidance for work packages to produce matrices to support vaccine thermostabilisation. We have also tested the matrix outputs from NIRI for thermostabilisation performance. |
Collaborator Contribution | NIRI have provided material science expertise in designing work packages to produce matrices to support vaccine thermostabilisation. |
Impact | The production of several generations of matrices and their testing for use in supporting vaccine thermostabilisation. This is a multidisciplinary project, drawing on material science, medicine, and vaccinology. |
Start Year | 2017 |
Description | Oxford - AstraZeneca COVID-19 vaccine |
Organisation | AstraZeneca |
Country | United Kingdom |
Sector | Private |
PI Contribution | I was one of 6 co-leaders of the Oxford COVID-19 vaccine development team. I led the development of the large-scale manufacturing process, and the assembly of a collaborative consortium of multiple partners to deliver it. We had initiated partnerships with & technology transfer to five manufacturing sites within Feb/Mar 2020, several weeks before the University's partnership with AZ (these five were Cobra & Oxford Biomedica in the UK, Halix in the Netherlands, Serum Institute of India, and Wuxi in China). The demonstration of a manufacturing process at a commercially relevant scale (through our partnership with Pall Biotech) was a critical element in securing the University's partnership with AZ. AZ adopted the template of 'franchised' multi-site manufacturing we had established, and added further manufacturing sites. The five manufacturing sites which my group had established pre-AZ, however, remained the core of the global manufacturing network - these five sites produced more than half of both UK & global supply of the vaccine. Early development of the manufacturing technology which enabled this work was done to enable production of my MRC DPFS-funded simian adenovirus-vectored rabies vaccine. The work was extended (increasing productivity) using the EPSRC Future Vaccine Manufacturing Research Hub (VaxHub) award. Scale-up to commercial scale was supported by the UKRI rapid-response COVID-19 funding award (Rapid development ... million dose scale). |
Collaborator Contribution | AZ became the global license holder for the COVID vaccine, taking over leadership of the manufacturing network my team had established & then extending it. |
Impact | Over 3 billion doses of vaccine were produced. The demonstration of a manufacturing process at a commercially relevant scale (enabled by MRC, then EPSRC, then UKRI funding, and enacted through our partnership with Pall Biotech) was a critical element in securing the University's partnership with AZ. AZ adopted the template of 'franchised' multi-site manufacturing we had established, and added further manufacturing sites. The five manufacturing sites which my group had established pre-AZ remained the core of the global manufacturing network - these five sites produced more than half of both UK & global supply of the vaccine. |
Start Year | 2020 |
Description | Rabies clinical trial collaboration with IHI, Tanzania |
Organisation | Ifakara Health Institute |
Country | Tanzania, United Republic of |
Sector | Charity/Non Profit |
PI Contribution | Working with the team at IHI to design and deliver the RAB002 phase Ib/II clinical trial of the ChAdOx2 RabG candidate rabies vaccine. |
Collaborator Contribution | This is a true collaboration where we work together to design and deliver on the clinical trial. |
Impact | The trial has full regulatory and ethical approval, and the first participants have been vaccinated. The trial is on going. |
Start Year | 2019 |
Description | Wistar |
Organisation | Wistar Institute |
Country | United States |
Sector | Charity/Non Profit |
PI Contribution | Intellectual inputs into overall project design, plans for clinical trials, and plans for associated output testing. |
Collaborator Contribution | Intellectual inputs into overall project design, plans for clinical trials, and plans for associated output testing. |
Impact | None to date. |
Start Year | 2017 |
Title | Oxford/AstraZeneca COVID-19 vaccine |
Description | Awards to the Douglas group enabled the manufacturing of the Oxford/AstraZeneca vaccine to take place for use in later stage clinical trials. |
Type | Therapeutic Intervention - Vaccines |
Current Stage Of Development | Market authorisation |
Year Development Stage Completed | 2021 |
Development Status | Under active development/distribution |
Clinical Trial? | Yes |
Impact | The impact of the Oxford/AstraZeneca COVID-19 have been well documented and are internationally significant. Awards to the Douglas group enabled the development of the manufacturing process required for later stage clinical trials, and global supply of the vaccine. |
Title | RAB001 clinical trial |
Description | Candidate rabies vaccine. This is the first in person, phase Ia clinical trial. Initial participants have completed the study, but further recruitment is taking place with an anticipated study end in July 2023. |
Type | Therapeutic Intervention - Vaccines |
Current Stage Of Development | Early clinical assessment |
Year Development Stage Completed | 2019 |
Development Status | Under active development/distribution |
Clinical Trial? | Yes |
Impact | The new process for manufacturing this vaccine has led to manufacutring of 2.5 billion doses of the Oxford-AstraZeneca COVID-19 vaccine. This is covered in more detail elsewhere. |
Title | RAB002 clinical trial |
Description | This is a candidate rabies vaccine (ChAdOx2 RabG). It has undergone testing in a phase I trial in the UK (RAB001), which is still on going. RAB002 has full ethical and regulatory approval, and has vaccinated it's first participants. Recruitment and follow up are ongoing. The study is expected to end in late 2023. |
Type | Therapeutic Intervention - Vaccines |
Current Stage Of Development | Early clinical assessment |
Year Development Stage Completed | 2021 |
Development Status | Under active development/distribution |
Clinical Trial? | Yes |
Impact | Nothing beyond what was reported for manufacturing the vaccine under the RAB001 entry. |
Title | Rabies vaccine (ChAdOx2 RabG) |
Description | The focus of this grant is the development of a new, single dose vaccine against rabies. Pre-clinical development is near completion, and GMP manufacture is currently taking place. Phase I clinical trials should begin in 2019/2020. |
Type | Therapeutic Intervention - Vaccines |
Current Stage Of Development | Refinement. Non-clinical |
Year Development Stage Completed | 2018 |
Development Status | Under active development/distribution |
Impact | Improved GMP manufacturing process at the Clinical BioManufacturing Facility (University of Oxford), where our vaccine is being made. |
Description | 'Can we make rabies history?' - Rabies elimination symposium at American Society of Tropical Medicine and Hygiene |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Professional Practitioners |
Results and Impact | Alexander Douglas (award PI) organised a symposium about rabies control and elimination at the American Society for Tropical Medicine & Hygiene, New Orleans, October 2018, inviting speakers from Scotland, Kenya and Peru. This was attended by around 50 people drawn from diverse backgrounds, with additional attendance via web-streaming / web archive- the meeting audience is broad, including public health practitioners, veterinarians, pharmaceutical industry personnel, non-governmental funders and press, and is the largest international meeting relating to global health. This was the first time a session about rabies has been organised at the meeting for several years- the key aim of the symposium was to raise the profile of rabies as a major public health problem and an important and neglected area for research and policy development. |
Year(s) Of Engagement Activity | 2018 |
Description | RAB002 press release and press |
Form Of Engagement Activity | A press release, press conference or response to a media enquiry/interview |
Part Of Official Scheme? | No |
Geographic Reach | Regional |
Primary Audience | Media (as a channel to the public) |
Results and Impact | RAB002 press release by the University. Led to an article in the local newspaper. |
Year(s) Of Engagement Activity | 2022 |
URL | https://www.ox.ac.uk/news/2022-03-04-rabies-vaccine-candidate-begins-human-trials-tanzania |